Hematological malignancies as well as many solid tumors harbor sub-populations of tumor-initiating cells that are important for tumor onset, progression, and malignancy. These multipotent tumor-initiating cells have the ability to proliferate and self-renew and are highly resistant to conventional chemotherapy and radiotherapy. In this proposal, we hypothesize that drug-resistant tumor-initiating cells exist in human mantle cell lymphoma (MCLs), and that they have the capacity to initiate the formation and progression of MCLs. MCL is aggressive B cell lymphoid malignancy and patients with MCL have median survival of two or three years. Conventional chemotherapy and radiation regimens are not curative for advanced MCL. The highly aggressive clinical behavior and low survival rates make MCL an ideal model for identification and characterization of tumor-initiating cells. Characterization of clonogenic populations that initiate MCL tumor formation will enable us to probe the pathology of these cells during tumor initiation and progression. These efforts may help the development of new preclinical models as well as the design of novel therapeutic strategies to treat or prevent the pathogenesis of MCLs in humans. PUBLIC HEALTH RELEVANCE: Non-Hodgkin's lymphomas (NHL) are the fifth most common cancer in the United States and the incidence of NHL has nearly doubled during the past three decades. However, cells initiating lymphoma have not been found. Therefore, we will use mantle cell lymphoma as a model to identify cells initiating proliferation of tumor cells and sustain tumor growth.